Compounds that inhibit factor xa activity

ABSTRACT

The present invention related to compounds of formula (I):  
                 
or pharmaceutically acceptable salts, hydrates or pharmaceutically acceptable formulations thereof. Those compounds can be used in inhibiting factor Xa and in the prevention and/or treatment of thromboembolic conditions.

The present invention relates to new compounds having an inhibitoryaction on blood clotting (so-called anticoagulants) and to theirpharmacologically acceptable salts and solvates and hydrates, topharmaceutical compositions comprising them as active ingredient, toprocesses for the preparation of such compounds, salts and compositions,and to the use thereof in the prevention and/or treatment ofthromboembolic conditions. Those compounds, salts and compositions arevery effective factor Xa inhibitors. The present invention relates alsoto pro-drugs, optically active forms, racemates and diastereoisomers ofthose compounds and salts.

Thromboembolic conditions are caused by an increased tendency to bloodclotting in people with risk factors, such as, for example relativelymajor operations, prolonged immobilisation, fractures of the lowerextremities, obesity, blood fat metabolism disorders, infections withgram-negative organisms, cancer and older age.

Venous thromboses may lead to the development of oedema or inflammationof the tissue drained by the affected vein. Thrombosis of a deeper vein(so-called deep vein thrombosis) may lead to serious complications, suchas, for example, pulmonary embolism. Arterial thrombosis may lead toischaemic necrosis of the tissue supplied by the affected artery, suchas, for example, to myocardial infarct in the case of anaffected:coronary artery. Other thromboembolic conditions are, forexample, arterio-sclerosis, apoplexy (stroke), angina pectoris,intermittent claudication.

Under normal physiological conditions, natural blood clotting protectsagainst major blood loss from a damaged blood vessel. During bloodclotting, liquid blood is converted into a blood clot, a gelatinous masswhich seals injured blood vessels by forming a plug. In that process,soluble fibrinogen present in the plasma is converted into thefibrous-gelatinous clotting substance fibrin in a multi-stage process,the so-called coagulation cascade.

A distinction is made between two different pathways of coagulationactivation. The intrinsic coagulation pathway is initiated when bloodcomes into contact with non-physiological surfaces. The extrinsiccoagulation pathway is initiated by injury to blood vessels. Bothcoagulation pathways join in a common pathway in which the coagulationfactor X, a serine protease, is converted into its active form (factorXa). Factor Xa, together with factor Va and Ca²⁺ in the so-calledprothrombinase complex, causes prothrombin to be converted into thrombinwhich in turn, by cleaving peptides from fibrinogen, releases fibrinmonomers, which are capable of coagulating to form fibrin fibres.Finally, factor XIII brings about cross-linking and thus stabilisationof the fibrin fibres.

Anticoagulants are used both for the prevention and for the treatment ofthromboembolic conditions. As far as anticoagulants in the narrowersense are concerned, a distinction is made between heparin, which isimmediately effective and which directly inhibits certain blood clottingfactors, and vitamin K antagonists (for example, coumarin derivatives).The latter inhibit the production in the liver of certain clottingfactors which is dependent on the presence of vitamin K, and begin totake effect only slowly. Other anticoagulant agents are thefibrinolytics, which bring about direct or indirect activation of thefibrinolytic system, and thrombocyte aggregation inhibitors, such as,for example, acetylsalicylic acid. A more seldom used method isreduction of the fibrinogen level in the blood by the enzyme ancrod. Theobject of using anticoagulant agents is to prevent the development of ablood clot that could close a vessel or also to dissolve it again onceit has formed.

The above-mentioned anticoagulants in the narrower sense, that is to sayheparin and vitamin K antagonists, have disadvantages. In the case ofheparin, a distinction is made between unfractionated heparin (UFH) andlow-molecular-weight heparin (LMWH). A disadvantage with UFH is the factthat it generally has to be administered intravenously, has a varyinganticoagulant effect and therefore necessitates frequent monitoring ofthe patient and adaptation of the dosage. Although LMWH can be usedsubcutaneously in a constant, unmonitored dosage, its effect, comparedto that of UFH, is greatly reduced because of its short chain length.

The vitamin K antagonists such as, for example, warfarin exhibit degreesof activity that differ from patient to patient, presumably owing togenetic factors. In addition to the slow onset of action mentionedabove, this is associated with the disadvantage that patients have to bemonitored and individual adaptation of the dosage is required.

Other known anticoagulants belong to the group of the thrombininhibitors. Current overviews of relevant research activity in thatfield can be found, for example, in Jules A. Shafer, Current Opinion inChemical Biology, 1988, 2: 458-485, Joseph P. Vacca, Current Opinion inChemical Biology, 2000, 4: 394-400 and also in Fahad Al-Obeidi and JamesA. Ostrem, DDT, Vol. 3, No. 5, May 1998: 223-231.

A crucial disadvantage of thrombin inhibitors is that, in order toobtain the desired effect, it is necessary to suppress thrombin activityin vivo to such a great extent that the tendency to haemorrhage mayincrease, which makes dosage difficult.

In contrast, factor Xa inhibitors cause suppression of the new formationof thrombin from prothrombin, whereas they do not impair existingthrombin activity which is necessary for primary haemostasis.

The spectra of action and side-effects of some of those factor Xainhibitors have not yet been fully investigated.

An object of the present invention was to provide new compounds havinguseful properties, especially an anticoagulating action.

More precisely, the object was to provide new factor Xa inhibitorshaving improved efficacy, reduced side-effects and/or increasedselectivity. In addition, suitable pharmaceutical compositions were tobe provided. Those compounds and compositions were to be administrablepreferably parenterally or orally, especially orally.

A further object of the present invention was to provide a process forthe preparation of those new compounds.

Those new compounds were furthermore to be suitable for use in theprevention and/or treatment of thromboembolic conditions.

The present invention describes anticoagulant compounds, theirpharmacologically acceptable salts and solvates and hydrates andformulations that have a high activity and selectivity and can beadministered especially orally. The present invention further relates topro-drugs, optically active forms, racemates and diastereoisomers ofthose compounds and salts. The said compounds and salts may alsothemselves be pro-drugs, which are activated only by metabolisation.Pharmaceutical compositions comprising the said compounds or salts etc.as active ingredient are also described.

The present invention relates to a compound of the general formula (I):

wherein

-   -   A is a hydrogen atom; a group of formula —NHC(═NR⁴)NH₂ or        —C(═NR⁴)NH₂, wherein R⁴ is a hydrogen atom, a heteroalkyl,        heteroaralkyl, heterocycloalkyl, heteroalkylcycloalkyl, hydroxy        or alkyloxy group, or R⁴, together with one of the radicals R¹,        is part of a 5- or 6-membered heteroaryl or heterocycloalkyl        ring; or A has one of the following structures:        Ar¹ is an aryl, aralkyl, heteroaryl or heteroaralkyl group,    -   Ar² is an aryl, aralkyl, heteroaryl or heteroaralkyl group,    -   the radicals R¹ are, each independently of any other(s), a        hydrogen atom, a hydroxy group, a C₁—, C₂—, C₃— or C₄- alkyloxy        group, an amino group, a C₁—, C₂—, C₃— or C₄-alkylamino group, a        C₁—, C₂—, C₃— or C₄-dialkylamino group, a cyano group or a        halogen atom;    -   the radicals R², each independently of any other(s), are a        hydrogen atom, a hydroxy group, a C₁—, C₂—, C₃— or C₄-alkyloxy        group, an amino group, a C₁—, C₂—, C₃— or C₄-group, a C₁—, C₂—,        C₃— or C₄-dialkylamino group,alkylamino a cyano group or a        halogen atom;    -   R³ is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl,        cycloalkyl, alkylcycloalkyl, heteroalkylcyclo-alkyl,        heterocycloalkyl, aralkyl or heteroaralkyl radical;    -   G is a glycosyl group;    -   X is a group of formula NR⁵, O, CONR⁵, NR⁵CO, CH₂NR⁵, S, SO,        SO₂, SO₂NH, NHSO₂, PO₂NH, NHPO₂, CH₂, CHMe or CO, wherein R⁵ is        a hydrogen atom, a C₁—, C₂—, C₃— or C₄-alkyl group, a C₁—, C₂—,        C₃— or C₄-heteroalkyl group, a C₇—, C₈—, C₉—, C₁₀—, C₁₁— or        C₁₂-aralkyl group, or a C₆—, C₇—, C₈—, C₉—, C₁₀—, C₁₁— or        C₁₂-heteroaralkyl group;    -   Y is a group of formula CONR⁶, COCONR⁶, NR⁶, O, NR⁶CO, S, SO,        SO₂, SO₂NH, NHSO₂, PO₂NH, NHPO₂, CH₂, CHMe or CO, wherein R⁶ is        a hydrogen atom, a C₁—, C₂—, C₃— or C₄-alkyl group, a C₁—, C₂—,        C₃— or C₄-heteroalkyl group or a C₇—, C₈—, C₉—, C₁₀—, C₁₁— or        C₁₂-aralkyl group;    -   n is 0, 1, 2, 3 or 4, and    -   m is 0, 1, 2, 3 or 4,    -   or a pharmacologically acceptable salt, solvate, hydrate or        pharmacologically acceptable formulation thereof.

The following definitions relate to the entire description and,especially, to the claims:

The expression alkyl refers to a saturated, straight-chain or branchedhydrocarbon group having, for example, from 1 to 20 carbon atoms,preferably from 1 to 12 carbon atoms, especially 1, 2, 3, 4, 5 or 6carbon atoms, for example a methyl, ethyl, propyl, isopropyl, isobutyl,tert-butyl, n-hexyl, 2,2-dimethylbutyl or n-octyl group.

The expression alkenyl refers to straight-chain or branched hydrocarbongroups containing at least one double bond and having from 2 to 20carbon atoms, preferably from 2 to 12 carbon atoms, especially 2, 3, 4,5, or 6 carbon atoms, for example an ethenyl, allyl, isoprenyl orhex-2-enyl group. They preferably have one or two (especially one)double bond(s).

The expression alkynyl refers to straight-chain or branched hydrocarbongroups containing at least one triple bond and having from 2 to 20carbon atoms, preferably from 2 to 12 carbon atoms, especially 2, 3, 4,5, or 6 carbon atoms, for example an ethynyl or propargyl group. Theypreferably have one or two (especially one) triple bond(s).

Furthermore, the terms alkyl, alkenyl and alkynyl refer to groups inwhich one, two, three or more hydrogen atoms have been replaced by ahalogen atom (preferably F or Cl) such as, for example, a2,2,2-trichloroethyl or trifluoromethyl group.

The expression heteroalkyl refers to an alkyl, alkenyl or alkynyl groupin which one or more (preferably 1, 2 or 3) carbon atoms have beenreplaced, each-independently of any other(s), by an oxygen, nitrogen,phosphorus, boron, selenium, silicon and/or sulphur atom (preferablyoxygen, sulphur or nitrogen). The expression heteroalkyl furthermorerefers to a carboxylic acid or to a group derived from a carboxylic acidsuch as, for example, acyl, acylalkyl, alkoxycarbonyl, acyloxy,acyloxyalkyl, carboxyalkylamide or alkoxycarbonyloxy.

Examples of heteroalkyl groups are groups of formulae R^(a)—O—Y^(a)—,R^(a)—S—Y^(a)—, R^(a)—N(R^(b))—Y^(a)—, R^(a)—CO—Y^(a)—,R^(a)—O—CO—Y^(a)—, R^(a)—CO—O—Y^(a)—, R^(a)—CO—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—CO—Y^(a)—, R^(a)—O—CO—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—CO—O—Y^(a)—, R^(a)—N(R^(b))—CO—N(R^(c))—Y^(a)—,R^(a)—O—OC—O—Y^(a)—, R^(a)—N(R^(b))—C(═NR^(d))—N(R^(c))—Y^(a),R^(a)—CS—Y^(a)—, R^(a)—O—CS—Y^(a)—, R^(a)—CS—O—Y^(a)—,R^(a)—CS—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CS—Y^(a)—,R^(a)—O—CS—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CS—O—Y^(a)—,R^(a)—N(R^(b))—CS—N(R^(c))—Y^(a)—, R^(a)—O—CS—O—Y^(a)—,R^(a)—S—CO—Y^(a)—, R^(a)—CO—S—Y^(a), R^(a)—S—CO—N(R^(b))—Y^(a)—,R^(a)—N(R^(b))—CO—S—Y^(a)—, R^(a)—S—CO—O—Y^(a)—, R^(a)—CO—S—Y^(a)—,R^(a)—S—CO—S—Y^(a)—, R^(a)—S—CS—Y^(a)—, R^(a)—CS—S—Y^(a)—,R^(a)—S—CS—N(R^(b))—Y^(a)—, R^(a)—N(R^(b))—CS—S—Y^(a)—,R^(a)—S—CS—O—Y^(a)—, R^(a)—O—CS—S—Y^(a)—, R^(a) being a hydrogen atom, aC₁—, C₂—, C₃—, C₄—, C₅— or C₆-alkyl, C₂—, C₃—, C₄—, C₅— or C₆-alkenyl orC₂—, C₃—, C₄—, C₅— or C₆-alkynyl group; R^(b) being a hydrogen atom, aC₁—, C₂—, C₃—, C₄—, C₅— or C₆-alkyl, C₂—, C₃—, C₄—, C₅— or C₆-alkenyl orC₂—, C₃—, C₄—, C₅— or C₆-alkynyl group; R^(c) being a hydrogen atom, aC₁—, C₂—, C₃—, C₄—, C₅— or C₆-alkyl, C₂—, C₃—, C₄—, C₅— or C₆-alkenyl orC₂—, C₃—, C₄—, C₅— or C₆-alkynyl group; R^(d) being a hydrogen atom, aC₁—, C₂—, C₃—, C₄—, C₅— or C₆-alkyl, C₂—, C₃—, C₄—, C₅— or C₆-alkenyl orC₂—, C₃—, C₄—, C₅— or C₆-alkynyl group and Y^(a) being a bond, a C₁—,C₂—, C₃—, C₄—, C₅— or C₆-alkylene, C₂—, C₃—, C₄—, C₅— or C₆-alkenyleneor C₂—, C₃—, C₄—, C₅— or C₆-alkynylene group, each heteroalkyl groupcontaining at least one carbon atom and it being possible for one, two,three or more hydrogen atoms to have been replaced by halogen atoms(especially fluorine or chlorine atoms). Specific examples ofheteroalkyl groups are methoxy, trifluoromethoxy, ethoxy, n-propyloxy,isopropyloxy, tert-butyloxy, methoxymethyl, ethoxymethyl, methoxyethyl,methylamino, ethylamino, dimethylamino, diethylamino,isopropylethylamino, methylaminomethyl, ethylaminomethyl,diisopropylaminoethyl, enol ether, dimethylaminomethyl,dimethylaminoethyl, acetyl, propionyl, butyryloxy, acetyloxy,methoxycarbonyl, ethoxycarbonyl, N-ethyl-N-methylcarbamoyl andN-methylcarbamoyl. Further examples of heteroalkyl groups are nitrile,isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate, carbonyland alkylnitrile groups.

The expression cycloalkyl refers to a saturated or partially unsaturated(for example, cycloalkenyl, cycloalkynyl) cyclic group having one ormore rings (preferably 1 or 2, especially 1) and containing a total offrom 3 to 14 ring carbon atoms, preferably from 3 to 10 (especially 3,4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl refersfurthermore to corresponding groups in which one or more hydrogen atomshave been replaced, each independently of any other(s), by fluorine,chlorine, bromine or iodine atoms or by OH, ═O, SH, ═S, NH₂, ═NH or NO₂groups, that is to say, for example, cyclic ketones such as, forexample, cyclohexanone, 2-cyclohexenone or cyclopentanone. Furtherspecific examples of cycloalkyl groups are a cyclopropyl, cyclobutyl,cyclopentyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl,cyclohexadienyl, decalinyl, cubanyl, bicyclo[4.3.0]nonyl,1,2,3,4-tetrahydronaphthyl, cyclo-pentylcyclohexyl, fluorocyclohexyl orcyclohex-2-enyl group.

The expression heterocycloalkyl refers to a cycloalkyl group as definedabove (for example, saturated or mono- or poly-unsaturated cycloalkylgroups such as cycloalkenyl groups) in which one or more (preferably 1,2 or 3) ring carbon atoms have been replaced, each independently of anyother(s), by an oxygen, nitrogen, silicon, selenium, phosphorus orsulphur atom (preferably oxygen, sulphur or nitrogen). Aheterocycloalkyl group has preferably 1 or 2 (especially 1) ring(s)containing from 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms. Theexpression heterocycloalkyl refers furthermore to corresponding groupsin which one or more hydrogen atoms have been replaced, eachindependently of any other(s), by fluorine, chlorine, bromine or iodineatoms or by OH, ═O, SH, ═S, NH₂, ═NH or NO₂ groups. Examples are apiperidyl, morpholinyl, urotropinyl, pyrrolidinyl, tetrahydrothiophenyl,tetra-hydropyranyl, tetrahydrofuryl, oxacyclopropyl, azacyclo-propyl or2-pyrazolinyl group and also lactams, lactones, cyclic imides and cyclicanhydrides.

The expression alkylcycloalkyl refers to groups containing bothcycloalkyl and also alkyl, alkenyl or alkynyl groups in accordance withthe above definitions. An alkylcyloalkyl group contains preferably oneor two (especially one) cycloalkyl group(s), each of which contains from3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or twoalkyl, alkenyl or alkynyl groups containing 1 or 2 to 6 carbon atoms.

Examples of such compounds are:

-   -   alkylcycloalkyl, alkyldicycloalkyl, dialkylcycloalkyl.        alkylcycloalkenyl, alkyldicycloalkenyl, dialkylcycloalkenyl,        alkenylcycloalkyl, alkenyldicycloalkyl, dialkyldicycloalkyl,        alkenylcycloalkenyl, alkenyldicycloalkenyl, dialkyldicycloalkyl,        dialkenylcycloalkyl, dialkenylcycloalkenyl, alkynylcycloalkyl,        alkynyldicycloalkyl, dialkenyldicycloalkyl, alkynylcycloalkenyl,        alkynyldicycloalkenyl, dialkenyldicycloalkenyl.

The expression heteroalkylcycloalkyl refers to alkylcycloalkyl groups asdefined above in which one or more (preferably 1, 2 or 3) carbon atomshave been replaced, each independently of any other(s), by an oxygen,nitrogen, silicon, selenium, phosphorus or sulphur atom (preferablyoxygen, sulphur or nitrogen). A heteroalkylcycloalkyl group containspreferably 1 or 2 (especially one) ring(s) each containing from 3 to 10(especially 3, 4, 5, 6 or 7) ring atoms and one or two alkyl, alkenyl,alkynyl or heteroalkyl groups each containing 1 or 2 to 6 carbon atoms.Examples of such groups, which may be substituted by alkyl, alkenyl,alkynyl and/or heteroalkyl groups, are:

-   -   heteroalkylcycloalkyl, heteroalkyldicycloalkyl,        diheteroalkylcycloalkyl, heteroalkylcycloalkenyl,        heteroalkyldicycloalkenyl, diheteroalkylcycloalkenyl,        heteroalkenylcycloalkyl, heteroalkenyldicycloalkyl,        diheteroalkyldicycloalkyl, heteroalkenylcycloalkenyl,        heteroalkenyldicycloalkenyl, diheteroalkyldicycloalkyl,        diheteroalkenylcycloalkyl, diheteroalkenylcycloalkenyl,        heteroalkynylcycloalkyl, heteroalkynyldicycloalkyl,        diheteroalkenyldicycloalkyl, heteroalkynylcycloalkenyl,        heteroalkynyldicycloalkenyl, diheteroalkenyldicycloalkenyl,        alkylheterocycloalkyl, alkyldiheterocycloalkyl,        dialkylheterocycloalkyl, alkylheterocycloalkenyl,        alkyldiheterocycloalkenyl, dialkylheterocycloalkenyl,        alkenylheterocycloalkyl, alkenyldiheterocycloalkyl,        dialkyldiheterocycloalkyl, alkenylheterocycloalkenyl,        alkenyldiheterocycloalkenyl, dialkyldiheterocycloalkyl,        dialkenylheterocycloalkyl, dialkenylheterocycloalkenyl,        alkynylheterocycloalkyl, alkynyldiheterocycloalkyl,        dialkenyldiheterocycloalkyl, alkynylheterocycloalkenyl,        alkynyldiheterocycloalkenyl, dialkenyldiheterocycloalkenyl,        heteroalkylheterocycloalkyl, heteroalkyldiheterocycloalkyl,        diheteroalkylheterocyclo-alkyl, heteroalkylheterocycloalkenyl,        heteroalkyldiheterocycloalkenyl,        diheteroalkylheterocycloalkenyl, heteroalkenylheterocycloalkyl,        heteroalkenyldiheterocyclo-alkyl,        diheteroalkyldiheterocycloalkyl,        heteroalkenylheterocycloalkenyl,        heteroalkenyldiheterocycloalkenyl,        diheteroalkyldiheterocycloalkyl,        diheteroalkenylheterocycloalkyl,        diheteroalkenylheterocycloalkenyl,        hetero-alkynylheterocycloalkyl, heteroalkynyldiheterocycloalkyl,        diheteroalkenyldiheterocycloalkyl,        heteroalkynylheterocycloalkenyl,        heteroalkynyldiheterocycloalkenyl,        diheteroalkenyldiheterocycloalkenyl.

Special preference is given to:

-   -   alkylheterocycloalkyl, alkylheterocycloalkenyl,        alkenylheterocycloalkyl, alkynylheterocycloalkyl,        heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and        heteroalkylheterocylcloalkenyl, the cyclic groups being        saturated or mono-, di- or tri-unsaturated.

The expression aryl or Ar refers to an aromatic group which has one ormore rings, preferably one ring, containing from 6 to 14 ring carbonatoms, preferably from 6 to 10 (especially 6) ring carbon atoms. Theexpression aryl (or Ar) refers furthermore to corresponding groups inwhich one or more hydrogen atoms have been replaced, each independentlyof any other(s), by fluorine, chlorine, bromine or iodine atoms or byOH, SH, NH₂ or NO₂ groups. Examples are a phenyl, naphthyl, biphenyl,2-fluorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.

The expression heteroaryl refers to an aromatic group which has one ormore rings, preferably one ring, containing from 5 to 14 ring atoms,preferably from 5, 6, 7, 8, 9 or 10 (especially 5 or 6) ring atoms, oneor more (preferably 1, 2, 3 or 4) ring atoms having been replaced byoxygen, nitrogen, phosphorus or sulphur ring atoms (preferably O, S orN). The expression heteroaryl refers furthermore to corresponding groupsin which one or more hydrogen atoms have been replaced, eachindependently of any other(s), by fluorine, chlorine, bromine or iodineatoms or by OH, SH, NH₂ or NO₂ groups. Examples are 4-pyridyl,2-imidazolyl, 3-phenylpyrrolyl, thiazolyl, oxazolyl, triazolyl,tetrazolyl, isoxazolyl, indazolyl, indolyl (for example, 6-indolyl),benzimidazolyl, pyridazinyl, quinolyl, purinyl, carbazolyl, acridinyl,pyrimidyl, 2,3-bifuryl, 3-pyrazolyl and isoquinolyl groups.

The expression aralkyl refers to groups containing both aryl and alsoalkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with theabove definitions such as, for example, arylalkyl, arylalkenyl,arylalkynyl, arylcycloalkyl, arylcycloalkenyl, arylcycloalkynyl,alkylarylcycloalkyl, alkylarylcycloalkenyl, alkylarylcycloalkynyl,alkylarylalkyl, alkylarylalkenyl, alkylarylalkynyl, alkenylarylalkenyl,alkynylarylalkenyl, alkynylarylalkynyl and arylalkylcycloalkyl groups.Specific examples of aralkyls are toluene, trityl, xylene, mesitylene,styrene, benzyl chloride, o-fluorotoluene, 1H-indene,1,2,3,4-tetra-hydronaphthyl, dihydronaphthalene, indanone,phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indan. Anaralkyl group preferably comprises an aromatic ring system (1 or 2rings) containing from 6 to 10 carbon atoms (for example, phenyl ornaphthyl) and one or two alkyl, alkenyl and/or alkynyl groups eachcontaining 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing5 or 6 ring carbon atoms.

The expression heteroaralkyl refers to an aralkyl group as defined abovein which one or more (preferably 1, 2, 3, or 4) carbon atoms have beenreplaced, each independently of any other(s), by an oxygen, nitrogen,silicon, selenium, phosphorus, boron or sulphur atom (preferably oxygen,sulphur or nitrogen), that is to say to groups containing both aryl orheteroaryl and also alkyl, alkenyl or alkynyl and/or heteroalkyl and/orcycloalkyl or cycloalkenyl, and/or heterocycloalkyl orheterocycloalkenyl groups in accordance with the above definitions. Aheteroaralkyl group preferably contains one or two aromatic ring systems(each comprising 1 or 2 rings) each containing 5, 6, 7, 8, 9 or 10 ringcarbon atoms and one or two alkyl, alkenyl and/or alkynyl groupscontaining 1 or 2, 3, 4, 5 or 6 carbon atoms and/or a cycloalkyl groupcontaining 5 or 6 ring carbon atoms, 1, 2, 3 or 4 or those carbon atomsand/or ring carbon atoms having been replaced, each independently of anyother(s), by oxygen, sulphur or nitrogen atoms.

Examples are aryl-heteroalkyl, aryl-heterocycloalkyl,aryl-heterocycloalkenyl, aryl-alkyl-heterocycloalkyl,aryl-alkenyl-heterocycloalkyl, aryl-alkynyl-heterocycloalkyl,aryl-alkyl-heterocycloalkenyl, aryl-heteroalkyl-heterocycloalkyl,heteroaryl-alkyl, heteroaryl-alkenyl, hetero-aryl-alkynyl,heteroaryl-heteroalkyl, heteroaryl-cycloalkyl, heteroaryl-cycloalkenyl,heteroaryl-heterocycloalkyl, heteroaryl-heterocycloalkenyl,heteroaryl-alkyl-cycloalkyl, heteroaryl-heteroalkyl-cycloalkyl,heteroaryl-alkyl-heterocycloalkenyl, heteroaryl-heteroalkyl-cycloalkenyland heteroaryl-heteroalkyl-heterocycloalkyl groups, the cyclic groupsbeing saturated or mono-, di- or tri-unsaturated. Specific examples area tetrahydro-isoquinolyl, benzoyl, 2- or 3-ethyl-indolyl,4-methyl-pyridino, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or4-carboxyphenylalkyl group.

The expressions cycloalkyl, aryl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, heteroaryl, aralkyl and heteroaralkyl refer togroups in which one or more hydrogen atoms have been replaced, eachindependently of any other(s), by fluorine, chlorine, bromine or iodineatoms or by OH, ═O, SH, ═S, NH₂, ═NH or NO₂ groups (the ═O, ═S and ═NHgroups in each case replacing two hydrogen atoms).

The expression “optionally substituted” refers to groups in which one,two or more hydrogen atoms have been replaced by fluorine, chlorine,bromine or iodine atoms or by OH, ═O, SH, ═S, SO₂NH₂, NH₂, ═NH or NO₂groups. The expression refers furthermore to groups in which one, two ormore hydrogen atoms have been replaced, each independently of anyother(s), by unsubstituted C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₁-C₆heteroalkyl, C₃-C₁₀cycloalkyl, C₂-C₉hetero-cycloalkyl, C₆-C₁₀aryl,C₁-C₉heteroaryl, C₇-C₁₂aralkyl or C₂-C₁₁heteroaralkyl groups.

In the present Application, the expression glycosyl group or glycosylradical refers to a saccharide (mono- or oligo-saccharide, includingamino sugars and N-acetylamino sugars) bonded by way of an α- or β-O—,—S—, —N— or —C-glycosidic bond (preferably an O-glycosidic bond),wherein the OH groups may optionally be protected by acetyl or benzoylgroups, especially a monosaccharide (for example, glucose, galactose,fructose, fucose, ribose, glucosamine, N-acetylglucosamine,galactosamine, N-acetylgalactosamine or mannose), preferablyβ-D-glucose.

Preference is given to compounds of the general formula (I) wherein Y isa group of formula CONR⁶ and R³ is not a group of formula—CHR⁷—CO—NR⁸R⁹, R⁷, R⁸ and R⁹ being, each independently of the others, ahydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, heteroaralkyl,heteroaryl, aralkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl or aryl group or R⁸ and R⁹ together being part ofa heterocycloalkyl or heteroaryl ring system.

Preference is furthermore given to compounds of the general formula (I)wherein Y is a group of formula CO and R³ is not a group of formula—NR¹⁰—CHR⁷—CO—NR⁸R⁹, R⁷, R , R⁹ and R¹⁰ being, each independently of theothers, a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl,heteroaralkyl, heteroaryl, alkylcycloalkyl, heteroalkyl-cycloalkyl,aralkyl, cycloalkyl, heterocycloalkyl or aryl group or R⁸ and R⁹ and/orR⁷ and R¹⁰ together being part of a heterocycloalkyl or heteroaryl ringsystem. Excluded, in particular, are compounds wherein the radical —Y—R³has the following structure:

-   -   —C(═O)—NR—CR′R″—C(═O)—N(R′″)R^(IV), the radicals R, R′, R″, R′″        and R^(IV) being defined as desired or denoting any desired        chemical radicals.

Preference is also given to Ar¹ not being a phenyl ring to which A and Xare bonded in positions para to one another when A is a group of formula—C(═NR⁴)NH₂ (especially ‘3C(═NH)NH₂).

Preference is furthermore given to A being a group of formula—C(═NR⁴)NH₂.

Preference is moreover given to A being a hydrogen atom.

Preference is also given to R⁴ being a hydrogen atom, a hydroxy or C₁—,C₂—, C₃— or C₄-alkyloxy group; special preference is given to R⁴ being ahydrogen atom.

Preference is furthermore given to Ar¹ being a phenyl group or aheteroaryl group containing 5, 6, 7, 8, 9 or 10 ring atoms and 1, 2, 3or 4 hetero atoms which are selected from O, S and N; special preferenceis given to Ar¹ being a phenyl group, especially a phenyl group to whichthe groups A and X are bonded in positions meta to one another.

Preference is moreover given to Ar² being a phenyl group or a heteroarylgroup containing 5 or 6 ring atoms and 1, 2 or 3 hetero atoms selectedfrom O, S and N; special preference is given to Ar² being a phenylgroup.

Preference is also given to X being a group of formula NH, NMe or NAc;special preference is given to X being an NH group.

Preference is moreover given to n being 0, 1 or 2, especially 0 or 1.

Preference is furthermore given to R¹ being a hydroxy group which, whenAr¹ is phenyl, is especially bonded in the position para to A.

Preference is also given to m being 0 or 1, the radicals R² and Gpreferably being in positions ortho to one another; special preferenceis given to m being 0.

Preference is furthermore given to Y being a group of formula CONH.

Preference is moreover given to R³ being a group of formula —U—V—W,wherein U is an optionally substituted arylene group containing 6 - 10or 12 ring carbon atoms or an optionally substituted heteroarylene groupcontaining 5, 6, 7, 8, 9 or 10 ring carbon atoms and 1, 2, 3 or 4(preferably 1 or 2) hetero: atoms selected from O, S and N; V is a bond,an oxygen atom, a sulphur atom, a group of formula NR¹¹ (R¹¹ being ahydrogen atom, a C₁—, C₂—, C₃— or C₄-alkyl group, a C₁—, C₂—, C₃— orC₄-heteroalkyl group, a C₇—, C₈—, C₉—, C₁₀—, C₁₁— or C₁₂-aralkyl groupor a C₆—, C₇—, C₈—, C₉—, C₁₀—, C₁₁— or C₁₂-heteroaralkyl group) , CO,SO, SO₂ or SO₂NH, and W is a hydrogen atom, an alkyl, alkenyl, alkynyl,heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl,heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkylradical.

Special preference is given to U being an optionally substitutedphenylene group, especially a para-phenylene group.

Special preference is moreover given to V being a bond or a carbonylgroup.

Special preference is also given to W being a C₁—, C₂—, C₃— or C₄-alkylgroup, a C₁—, C₂—, C₃— or C₄-heteroalkyl group containing one or two O,N or S atoms, an optionally substituted phenyl group, an optionallysubstituted C₃—, C₄—, C₅—, C₆— or C₇-cycloalkyl group, an optionallysubstituted heterocycloalkyl group containing 3-7 (preferably 5 or 6)ring carbon atoms and 1, 2 or 3 ring hetero atoms (selected, eachindependently of any other(s), from O, S and N) or an optionallysubstituted heteroaryl group containing 5 or 6 ring carbon atoms and 1,2, 3 or 4 ring hetero atoms selected from O, S and N.

Preference is given to compounds of the general formula I wherein Y is agroup of formula CONR⁶ and R³ is not a group of formula —CHR⁷—CO—NR⁸R⁹ ,R⁷, R⁸ and R⁹ being as defined for R⁵, R⁶ and R⁷ in the PCT ApplicationPCT/EP 02/01934 (WO 02/068390) of the company Morphochem AG of 22nd Feb.2002 or R⁷, R⁸ and R⁹ being as defined for R⁵, R⁶ and R⁷ in the PCTApplication PCT/EP 01/09753 (WO 02/16312) of the company Morphochem AGof 23rd Aug. 2001.

Special preference is given to compounds of formula (II):

wherein E is a hydrogen, fluorine, chlorine or bromine atom and theradicals R¹, R², G, V and W are as defined hereinbefore, o is 0 or 1, pis 0 or 1, and q is 0, 1 or 2. Special preference is given to R¹ being ahydroxy group, R² being a methoxy or ethoxy group, G being aβ-D-glucosyloxy group and V being a bond or a carbonyl group (C═O).

Special preference is given to W being a cyclic group of formula—N(CH₂CH₂)₂Q wherein Q is an oxygen atom or a group of formula NR¹², R¹²being a hydrogen atom, a C₁—, C₂—, C₃— or C₄-alkyl or C₁—, C₂—, C₃— orC₄-heteroalkyl radical (for example, a group of formula —C(═N)NH₂ or—C(═N)CH₃).

Preference is furthermore given to compounds of formula (I) (whereinU=phenyl) or (II) wherein V is a bond and W is a phenylene groupsubstituted by a group of formula SO₂NH₂ or SO₂alkyl in the positionortho to V.

Preference is moreover given to compounds of formula (I) wherein A andAr¹ together are an indole group to which the group X is bondedpreferably in the 6-position.

Preference is also given to compounds of formula (I) wherein n is 0, Aand Ar¹ together are a 6-indolyl group, X is CONH, m is 0, Ar² is aphenyl radical, Y is CO and R³ is a heterocycloalkyl orheteroalkylcycloalkyl group (especially a group of formula—N(CH₂CH₂)₂CH—CH(CH₂CH₂)₂NMe); special preference is given in this caseto the stereochemistry at the phenylglycine entity being (R).

Owing to their substitution, compounds of formula (I) or (II) containone or more centres of chirality. The present invention thereforeincludes both all pure enantiomers and all pure diastereoisomers andalso mixtures thereof in any mixing ratio. The present inventionmoreover also includes all cis/trans-isomers of the compounds of thegeneral formula (I) or (II) and also mixtures thereof. The presentinvention moreover includes all tautomeric forms of the compounds offormula (I) or (II).

Examples of pharmacologically acceptable salts of compounds of formula(I) or (II) are salts of physiologically acceptable mineral acids, suchas hydrochloric acid, sulphuric acid and phosphoric acid; or salts oforganic acids, such as methanesulphonic acid, p-toluenesulphonic acid,lactic acid, formic acid, acetic acid, trifluoro-acetic acid, citricacid, succinic acid, fumaric acid, maleic acid and salicylic acid.Compounds of formula (I) or (II) can be solvated, especially hydrated.The hydration may take place, for example, during the preparationprocess or as a consequence of the hygroscopic nature of the initiallyanhydrous compounds of formula (I) or (II).

The pharmaceutical compositions according to the present inventioncomprise at least one compound of formula (I) or (II) as activeingredient and optionally carrier substances and/or adjuvants.

The pro-drugs (for example, B. R. B. Silverman, Medizinische Chemie, VCHWeinheim, 1995, Chapter 8, p. 361ff), to which the present inventionalso relates consist of a compound of formula (I) or (II) and at leastone pharmacologically acceptable protecting group that is removed underphysiological conditions, for example a hydroxy, alkoxy, aralkyloxy,acyl or acyloxy group, such as, for example, a methoxy, ethoxy,benzyloxy, acetyl or acetyloxy group.

The compounds of formulae (I) and (II) described herein can be preparedaccording to methods known per se. Compounds of formulae (I) and (II)according to the invention can be prepared, for example, by reaction ofcompounds of formulae (III) (where appropriate, in hydrochloride form orin the form of a similar salt), (IV) and (V) using a multi-componentreaction (A. Dömling, I. Ugi, Angew. Chem. 2000, 112, 3300-3344), theradicals being defined as above. In the process, a compound of formula(III) is preferably dissolved together with a compound of formula (IV)especially in a suitable solvent (preferably a mixture of acetonitrileand water) and, where appropriate, stirred (preferably for 30 minutes atroom temperature). A compound of formula (V) is then added and, whereappropriate, further stirring is carried out (preferably for 15 hours atroom temperature). The optionally present solvent is then removedpreferably in vacuo. The compounds prepared in the process can bepurified, for example, by means of HPLC and separated into theindividual stereoisomers. Where appropriate, it may be preferred tocarry out the reaction in the presence of a Lewis acid (for example,indium trichloride, boron trifluoride etherate, trimethyl aluminium,lithium chloride, aluminium trichloride, scandium triflate, zincchloride, ytterbium triflate, magnesium triflate, magnesium bromide,zirconium chloride, titanium(IV) chloride or tin tetrachloride) or aBronsted acid. In the case of the compounds, obtained in that manner itwas found that both the compounds of formula (I) and (II) having an (R)configuration at the phenylglycine entity and also the corresponding(S)-configured compounds are very effective factor Xa inhibitors, the(S)-configured compounds having, when identically substituted, slightlybetter inhibitory properties. Preference is therefore given inaccordance with the invention to compounds of formula (I) and (II)having an (S) configuration, whilst compounds having an (R)configuration, and also mixtures in any mixing ratio, also have verygood inhibitory properties and this invention relates also thereto.

Alternatively, compounds of formula (I) or (II) can be prepared, forexample, analogously to the methods described in WO0230880, WO02057236,WO0112600, WO0071493, WO0071508, WO0071507, WO0035858, WO02068390,WO0216312 and WO0190051.

3-Aminobenzamidine is commercially available;3-amino-4-hydroxybenzamidine can be prepared from commercially available4-hydroxy-3-nitrobenzonitrile by means of a Pinner reaction (A. Pinner,F. Klein, Ber. 10, 1889 (1877); 11, 4, 1475 (1878); 16, 352, 1643(1883)) resulting in 4-hydroxy-3-nitro-benzamidine and subsequentreduction with H₂—Pd/C. Further benzamidines (such as, for example,3-amino-4-chloro-benzamidine) can also be prepared analogously.

Glycosylated aryl compounds (for example, glycosylated benzaldehydes)can be prepared, for example, by the processes described in Kleine etal. Carbohydrate Research 1985, 142, 333-337 and Brewster et al.Tetrahedron Letters 1979, 5051-5054.

Helicin (salicylaldehyde-β-D-glucoside) is commercially available.

A compound or pharmaceutical composition of the present invention can beused in inhibiting factor Xa activity, in the prevention and/ortreatment of thromboembolic conditions, arterial restenosis,septicaemia, cancer, acute inflammation or other conditions mediated byfactor X_(a) activity, and especially venous thromboses, oedema orinflammation, deep vein thrombosis, pulmonary embolisms, thromboemboliccomplications after relatively major operations, in the case of vascularsurgery, prolonged immobilisation, fractures of the lower extremitiesetc., arterial thromboses, especially of the coronary vessels in theevent of myocardial infarct, and arteriosclerosis, stroke, anginapectoris, intermittent claudication, to, mention but a few indications.

In general, as mentioned at the beginning, the active ingredientsaccording to the invention are to have an inhibitory action towardsfactor Xa that is as great as possible while having a selectivity thatis as high as possible. The selectivity was assessed in the present caseby comparing the inhibitory action towards factor Xa and also tryptase,trypsin, plasmin, thrombin and further serine proteases. Furthermore,the present compounds according to-the invention are of interest asinhibitors of further enzymes of the coagulation cascade (extrinsic andintrinsic) such as, for example, factor II, factor VII, factor VIIa,factor IX, factor IXa and factor X.

As mentioned above, the therapeutic use of the compounds of formula (I)or (II), of their pharmacologically acceptable salts and solvates andhydrates and also formulations and pharmaceutical compositions lieswithin the scope of the present invention.

The present invention relates also to the use of those activeingredients in the preparation of medicaments for the prevention and/ortreatment of thromboembolic conditions. In general, compounds of formula(I) or (II) are administered either individually or in combination withany other desired therapeutic agent, using the known and acceptablemethods. Administration may be effected, for example, by one of thefollowing routes: orally, for example in the form of dragees, coatedtablets, pills, semi-solid substances, soft or hard capsules, solutions,emulsions or suspensions; parenterally, for example in the form of aninjectable solution; rectally in the form of suppositories; byinhalation, for example in the form of a powder formulation or spray,transdermally or intranasally. For the preparation of such tablets,pills, semi-solid substances, coated tablets, dragees and hard gelatincapsules, the therapeutically usable product can be mixed withpharmacologically inert, inorganic or organic pharmaceutical carriersubstances, for example with lactose, sucrose, glucose, gelatin, malt,silica gel, starch or derivatives thereof, talcum, stearic acid or saltsthereof, skimmed milk powder and the like. For the preparation of softcapsules, pharmaceutical carrier substances such as, for example,vegetable oils, petroleum, animal or synthetic oils, wax, fat andpolyols can be used. For the preparation of liquid solutions and syrups,pharmaceutical carrier substances such as, for example, water, alcohols,aqueous saline solution, aqueous dextrose, polyols, glycerol, vegetableoils, petroleum and animal or synthetic oils can be used. Forsuppositories, pharmaceutical carrier substances such as, for example,vegetable oils, petroleum, animal or synthetic oils, wax, fat andpolyols can be used. For aerosol formulations, compressed gases that aresuitable for the purpose can be used, such as, for example, oxygen,nitrogen and carbon dioxide. The pharmaceutically acceptable agents mayalso comprise additives for preserving and stabilising, emulsifiers,sweeteners, flavourings, salts for altering the osmotic pressure,buffers, encapsulation additives and anti-oxidants.

Combinations with other therapeutic agents may comprise other activeingredients that are customarily used for the prevention and/ortreatment of thromboembolic conditions, such as, for example, warfarinetc.

For the prevention and/or treatment of the conditions mentioned above,the dose of the biologically active compound according to the inventioncan vary within wide limits and can be adjusted to individualrequirements. In general, a dose of from 0.1 μg to 10 mg/kg of bodyweight per day is suitable, a preferred dose being from 0.1 to 4 mg/kgper day. In suitable cases, the dose may also be below or above thestated values.

The daily dose can be administered in, for example, 1, 2, 3 or 4individual doses. It is also possible to administer the dose as a singledose for, for example, one week.

The following Examples are intended to illustrate the invention. Thestereochemistry of3,4,5-trihydroxy-6-hydroxymethyl-tetrahydropyran-2-yloxy corresponds tothat of β-D-glucose, and that of Examples 58, 59 and 60 corresponds tothat of β-D-galactose.

EXAMPLES

General procedure:

1 mmol of amine (II) and 1 mmol of aldehyde (III) are stirred in 20 mlof acetonitrile/water (mixing ratio of from 1:0 to 1:1) for 30 minutesat room temperature. 1 mmol of isonitrile (IV) is then added andstirring is carried out for a further 15 hours. The solvent is removedin vacuo and the residue is purified by means of HPLC.

Example 12-(3-Carbamimidoyl-phenylamino)-N-(2-trifluoromethyl-benzyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₁F₃N₄O₇ (604.5882) ESI-TOF MS: 605 [M+H]

Example 22-(3-Carbamimidoyl-phenylamino)-N-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₂N₄O₉ (580.5998) ESI-TOF MS: 581 [M+H]

Example 32-(3-Carbamimidoyl-phenylamino)-N-[3-(2-oxo-pyrrolidin-1-yl)-propyl]-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₈H₃₇N₅O₈ (571.6358) ESI-TOF MS: 572 [M+H]

Example 42-(3-Carbamimidoyl-phenylamino)-N-(4-phenoxy-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl3-acetamide

C₃₃H₃₄N₄O₈ (614.6609) ESI-TOF MS: 615 [M+H]

Example 52-(3-Carbamimidoyl-phenylamino)-N-(3,3-diphenyl-propyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₆H₄₀N₄O₇ (640.7428) ESI-TOF MS: 641 [M+H]

Example 62-(3-Carbamimidoyl-phenylamino)-N-(3-phenoxy-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₃H₃₄N₄O₈ (614.6609) ESI-TOF MS: 615 [M+H]

Example 72-(3-Carbamimidoyl-phenylamino)-N-(4-methoxy-biphenyl-3-yl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₄H₃₆N₄O₈ (628.6880) ESI-TOF MS: 629 [M+H]

Example 82-(3-Carbamimidoyl-phenylamino)-N-(4-morpholin-4-yl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₃₇N₅O₈ (607.6692) ESI-TOF MS: 608 [M+H]

Example 92-(3-Carbamimidoyl-phenylamino)-N-(4-benzoyl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₄H₃₄N₄O₈ (626.6721) ESI-TOF MS: 627 [M+H]

Example 102-(3-Carbamimidoyl-phenylamino)-N-(3-benzoyl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₄H₃₄N₄O₈ (626.6721) ESI-TOF MS: 627 [M+H]

Example 112-(3-Carbamimidoyl-phenylamino)-N-(4-tert-butyl-benzyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₂H₄₀N₄O₇ (592.6982) ESI-TOF MS: 593 [M+H]

Example 122-(2-Hydroxy-5-carbamimidoyl-phenylamino)-N-(4-morpholin-4-yl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₃₇N₅O₉ (623.6686) ESI-TOF MS: 624 [M+H]

Example 132-(3-Carbamimidoyl-phenylamino)-N-(3-methoxy-benzyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₄N₄O₈ (566.6163) ESI-TOF MS: 567 [M+H]

Example 14N-(4-Acetyl-phenyl)-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₂N₄O₈ (564.6004) ESI-TOF MS: 565 [M+H]

Example 152-(3-Carbamimidoyl-phenylamino)-N-(3-trifluoromethyl-benzyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₁F₃N₄O₇ (604.5882) ESI-TOF MS: 605 [M+H]

Example 162-(3-Carybamimidoyl-phenylamino)-N-(2-cyclohex-1-enyl-ethyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₈N₄O₇ (554.6488) ESI-TOF MS: 555 [M+H]

Example 172-(3-Carbamimidoyl-phenylamino)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₃₈N₄O₉ (610.6699) ESI-TOF MS: 611 [M+H]

Example 182-(3-Carbamimidoyl-phenylamino)-N-(3-morpholin-4-yl-propyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₈H₃₉N₅O₈ (573.6517) ESI-TOF MS: 574 [M+H]

Example 192-(3-Carbamimidoyl-phenylamino)-N-(4-trifluoromethyl-benzyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₁F₃N₄O₇ (604.5882) ESI-TOF MS: 605 [M+H]

Example 20N-[1-(4-Bromo-phenyl)-ethyl]-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₃BrN₄O₇ (629.5130) ESI-TOF MS: 630 [M+H]

Example 21N-Benzo[1,3]dioxol-5-ylmethyl-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₂N₄O₉ (580.5998) ESI-TOF MS: 581 [M+H]

Example 222-(3-Carbamimidoyl-phenylamino)-N-(3-phenyl-propyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₀H₃₆N₄O₇ (564.6440) ESI-TOF MS: 565 [M+H]

Example 232-(3-Carbamimidoyl-phenylamino)-N-(3,5-dimethyl-benzyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₀H₃₆N₄O₇ (564.6440) ESI-TOF MS: 565 [M+H]

Example 242-(3-Carbamimidoyl-phenylamino)-N-(3-cyano-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₈H₂₉N₅O₇ (547.5726) ESI-TOF MS: 548 [M+H]

Example 252-(3-Carbamimidoyl-phenylamino)-N-(3,4-dichloro-benzyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₈H₃₀C₁₂N₄O₇ (605.4799) ESI-TOF MS: 606 [M+H]

Example 26N-(3-Acetyl-phenyl)-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₂N₄O₈ (564.6004) ESI-TOF MS: 565 [M+H]

Example 272-(3-Carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-N-(1,2,2-trimethyl-propyl)-acetamide

C₂₇H₃₈N₄O₇ (530.6265) ESI-TOF MS: 531 [M+H]

Example 28N-Allyl-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₄H₃₀N₄O₇ (486.5293) ESI-TOF MS: 487 [M+H]

Example 29N-(3-Butoxy-propyl)-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₈H₄₀N₄O₈ (560.6530) ESI-TOF MS: 561 [M+H]

Example 302-(3-Carbamimidoyl-phenylamino)-N-(3,7-dimethyl-octa-2,6-dienyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₄₂N₄O₇ (582.7030) ESI-TOF MS: 583 [M+H]

Example 312-(3-Carbamimidoyl-phenylamino)-N-furan-2-ylmethyl-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₆H₃₀N₄O₈ (526.5510) ESI-TOF MS: 527 [M+H]

Example 322-(3-Carbamimidoyl-phenylamino)-N-(3-isopropoxy-propyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₇H₃₈N₄O₈ (546.6259) ESI-TOF MS: 547 [M+H]

Example 333-{2-(3-Carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetylamino}-propionicacid ethyl ester

C₂₆H₃₄N₄O₉ (546.5823) ESI-TOF MS: 547 [M+H]

Example 34N-tert-Butyl-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₅H₃₄N₄O₇ (502.5723) ESI-TOF MS: 503 [M+H]

Example 352-(3-Carbamimidoyl-phenylamino)-N-pyridin-4-ylmethyl-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₇H₃₁N₅O₇ (537.5774) ESI-TOF MS: 538 [M+H]

Example 362-(3-Carbamimidoyl-phenylamino)-N-methyl-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₂H₂₈N₄O₇ (460.4911) ESI-TOF MS: 461 [M+H]

Example 372-(3-Carbamimidoyl-phenylamino)-N-(1,3-dimethyl-butyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₇H₃₈N₄O₇ (530.6265) ESI-TOF MS: 531 [M+H]

Example 38N-(4-Benzoyl-phenyl)-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₄H₃₄N₄O₈ (626.6721) ESI-TOF MS: 627 [M+H]

Example 392-(5-Carbamimidoyl-2-hydroxy-phenylamino)-N-(4-morpholin-4-yl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxy-methyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₃₇N₅O₉ (623.6686) ESI-TOF MS: 624 [M+H]

Example 402-(3-Carbamimidoyl-phenylamino)-N-(2,6-dimethyl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₄N₄O₇ (550.6169) ESI-TOF MS: 551 [M+H]

Example 412-(3-Carbamimidoyl-phenylamino)-N-(4-nitro-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C27H29N5O9 (567.5603) ESI-TOF MS: 568 [M+H]

Example 42N-(4-Amino-phenyl)-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C27H31N5O7 (537.5774) ESI-TOF MS: 538 [M+H]

Example 432-{2-(3-Carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetylamino}-benzoicacid methyl ester

C₂₉H₃₂N₄O₉ (580.5998) ESI-TOF MS: 581 [M+H]

Example 442-(5-Carbamimidoyl-2-chloro-phenylamino)-N-(4-morpholin-4-yl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxy-methyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₃₆ClN₅O₈ (642.1143) ESI-TOF MS: 643 [M+H]

Example 452-(3-Carbamimidoyl-phenylamino)-N-[4-(morpholin-4-carbonyl)-phenyl]-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₂H₃₇N₅O₉ (635.6798) ESI-TOF MS: 636 [M+H]

Example 462-(5-Carbamimidoyl-2-methylamino-phenylamino)-N-(4-morpholin-4-yl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₂H₄₀N₆O₈ (636.7110) ESI-TOF MS: 637 [M+H]

Example 47N-(2-Bromo-phenyl)-2-(3-carbamimidoyl-phenyl-amino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₇H₂₉BrN₄O₇ (601.4588) ESI-TOF MS: 602 [M+H]

Example 482-{2-(3-Carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetylamino}-benzoicacid

C₂₈H₃₀N₄O₉ (566.5727) ESI-TOF MS: 567 [M+H]

Example 492-(3-Carbamimidoyl-phenylamino)-N-quinolin-6-yl-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₀H₃₁N₅O₇ (573.6109) ESI-TOF MS: 574 [M+H]

Example 502-{2-{3-[N-(3-Fluoro-benzyl)-carbamimidoyl]-phenylamino}-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetylamino}-benzoicacid methyl ester

C₃₆H₃₇FN₄O₉ (688.7161) ESI-TOF MS: 689 [M+H]

Example 51N-(2-Benzoyl-4-chloro-phenyl)-2-(3-carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₄H₃₃ClN₄O₈ (661.1171) ESI-TOF MS: 662 [M+H]

Example 522-(3-Carbamimidoyl-phenylamino)-N-[3-chloro-4-(morpholin-4-carbonyl)-phenyl]-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₂H₃₆ClN₅O₉ (670.1248) ESI-TOF MS: 671 [M+H]

Example 532-(3-Carbamimidoyl-phenylamino)-N-[2-methyl-4-(morpholin-4-carbonyl)-phenyl]-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₃H₃₉N₅O₉ (649.7069) ESI-TOF MS: 650 [M+H]

Example 542-(5-Carbamimidoyl-2-hydroxy-phenylamino)-N-[4-(morpholin-4-carbonyl)-phenyl]-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₂H₃₇N₅O₁₀ (651.6792) ESI-TOF MS: 652 [M+H]

Example 552-(3-Carbamimidoyl-phenylamino)-N-(3,4-difluoro-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₇H₂₈F₂N₄O₇ (558.5436) ESI-TOF MS: 559 [M+H]

Example 564-{2-(3-Carbamimidoyl-phenylamino)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetylamino}-benzoicacid methyl ester

C₂₉H₃₂N₄O₉ (580.5998) ESI-TOF MS: 581 [M+H]

Example 572-(3-Carbamimidoyl-phenylamino)-N-(3,4-dimethoxy-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₉H₃₄N₄O₉ (582.6157) ESI-TOF MS: 583 [M+H]

Example 58 Acetic acid3,4,5-triacetoxy-6-{2-[(5-carbamimidoyl-2-hydroxy-phenylamino)-(4-morpholin-4-yl-phenylcarbamoyl)-methyl]-phenoxy}-tetrahydro-pyran-2-ylmethylester

C₃₉H₄₅N₅O₁₃ (791.8192) ESI-TOF MS: 792 [M+H]

Example 592-(3-Carbamimidoyl-phenylamino)-N-(4-morpholin-4-yl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxy-methyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₃₇N₅O₈ (607.6692) ESI-TOF MS: 608 [M+H]

Example 602-(5-Carbamimidoyl-2-hydroxy-phenylamino)-N-(4-morpholin-4-yl-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₃₁H₃7N₅O₉ (623.6686) ESI-TOF MS: 624 [M+H]

Example 612-(3-Carbamimidoyl-phenylamino)-N-(4-methoxy-phenyl)-2-[2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-acetamide

C₂₈H₃₂N₄O₈ (552.5892) ESI-TOF MS: 553 [M+H]

Example 622-(3-Carbamimidoyl-phenylamino)-2-[3-ethoxy-2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-N-[4-(morpholine-4-carbonyl)-phenyl]-acetamide

C₃₄H₄₁N₅O₁₀ (679.7334) ESI-TOF MS: 680 [M+H]

Example 632-(3-Carbamimidoyl-phenylamino)-2-[3-ethoxy-2-(3,4,5-trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-yloxy)-phenyl]-N-(4-morpholin-4-yl-phenyl)-acetamide

C₃₃H₄₁N₅O₉ (651.7228) ESI-TOF MS: 652 [M+H]

In order to demonstrate the inhibitory action towards factor Xaactivity, chromogenic peptide substrates were used. The inhibition ofthe amidolytic activity of factor Xa by the compounds described abovewas demonstrated as follows. The measurements were carried out inmicrotitre plates at room temperature. The compounds were dissolved indimethyl sulphoxide and 5 μl of the solution (1 mM, 100 μM, 10 μM, 1 μM)were added to 35 μml of a 2.15 nM solution of human recombinant factorXa (Enzyme Research Laboratories, South Bend, Ind., USA) in a buffer(pH: 8.0 and using 50 mM Tris-HCl, 100 mM NaCl, 0.1% PEG 6000 and 0.05%Tween 80). Finally, 10 μl of a 25 μM MeSO₂-D-CHA-Gly-Arg-AMC acetatesolution (“Spectrozym fXa”, American Diagnostica, Pfungstadt, Germany)in buffer were added and the hydrolysis of the substrate was monitoredwith a Spectra Fluor Plus spectrophotometer (Tecan, Crailsheim, Germany)over a period of 20 minutes at the following wavelengths: excitation:360 nm, emission: 465 nm. The IC₅₀ values were calculated by means ofthe “GraFit 4” program of the company Erithacus Software Ltd. (Staines,Middlesex, UK). On the assumption that the kinetics comprise acompetitive inhibition, it was possible to determine the Ki value by theCheng-Prusoff equation: Ki=IC₅₀/(1+[S]/K_(m)]) (Cheng and Prusoff,Biochemical Pharmacology 1973, 22: 3099-3108). The same procedure, butwith tosyl-glycyl-prolyl-lysine-4-nitranilide acetate being used as thesubstrate in Hepes buffer (pH 7.8), was used to determine the inhibitionof the proteolytic activity of recombinant human tryptase (Promega,Madison, Wis., USA) by the said compounds.

The IC₅₀ values of the above-mentioned Examples are in the range from0.1 nM to 1 μM.

1. A compound comprising formula (I):

wherein A is a hydrogen atom; a group of formula —C(═NR⁴)NH₂, wherein R⁴ is a hydrogen atom, a heteroalkyl, hetero-aralkyl, heterocycloalkyl, heteroalkylcycloalkyl, hydroxy or alkyloxy group or is, together with one of the radicals R¹, part of a 5- or 6-membered heteroaryl or heterocycloalkyl ring; a group of formula —NHC(═NR⁴)NH₂; or has one of the following structures:

Ar¹ is an aryl, aralkyl, heteroaryl or heteroaralkyl group, Ar² is an aryl, aralkyl, heteroaryl or heteroaralkyl group, the radicals R¹ are, each independently of any other(s), a hydroxy group, a C₁-C₄alkyloxy group, an amino group, a C₁-C₄alkylamino group, a C₁-C₄-dialkylamino group, a cyano group or a halogen atom; the radicals R², each independently of any other(s), are a hydroxy group, a C₁-C₄alkyloxy group, an amino group, a C₁-C₄alkylamino group, a C₁-C₄-dialkylamino group, a cyano group or a halogen atom; R³ is an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkyl-cycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl radical; G is a glycosyl group; X is a group of formula NR⁵, O, CONR⁵, NR⁵CO, CH₂NR⁵, S, SO, SO₂, SO₂NH, NHSO₂, PO₂NH, NHPO₂, CH₂, CHMe or CO, wherein R⁵ is a hydrogen atom, a C₁-C₄alkyl, C₁-C₄-heteroalkyl, C₇-C₁₂aralkyl or C₆-C₁₂heteroaralkyl group; Y is a group of formula CONR⁶, COCONR⁶, NR⁶, O, NR⁶CO, S, SO, SO₂, SO₂NH, NHSO₂, PO₂NH, NHPO₂, CH₂, CHMe or CO, wherein R⁶ is a hydrogen atom, a C₁-C₄alkyl, C₁-C₄-heteroalkyl or C₇-C₁₂aralkyl group; n is 0, 1, 2, 3 or 4, and m is 0, 1, 2, 3 or 4, or a pharmacologically acceptable salt, solvate, hydrate or pharmacologically acceptable formulation thereof, there being excluded compounds in which Y is a group of formula CONR⁶ and R³ is a group of formula —CHR⁷—CO—NR⁸R⁹, R⁷, R⁸ and R⁹ being, each independently of the others, a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, heteroaralkyl, heteroaryl, aralkyl, cycloalkyl, heterocycloalkyl, alkylcyclo-alkyl, heteroalkylcycloalkyl or aryl group, or R⁸ and R⁹ together are part of a heterocycloalkyl or heteroaryl ring system; there furthermore being excluded compounds wherein Y is a group of formula CO and R3 is a group of formula —NR¹⁰—CHR⁷—CO—NR⁸R⁹, R⁷, R⁸, R⁹ and R¹⁰ being, each independently of the others, a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, heteroaralkyl, heteroaryl, alkylcyclo-alkyl, heteroalkyl-cycloalkyl, aralkyl, cycloalkyl, heterocycloalkyl or aryl group, or R⁸ and R⁹ and/or R⁷ and R¹⁰ together are part of a heterocycloalkyl or heteroaryl ring system.
 2. Compounds according to claim 1, wherein A is a group of formula —C(═NH)NH₂.
 3. Compounds according to claim 1, wherein Ar¹ is a phenyl or heteroaryl group having 5, 6, 7, 8, 9 or 10 carbon ring atoms and 1, 2, 3 or 4 ring hetero atoms selected from O, S and N.
 4. Compounds according to claim 1, wherein Ar¹ is a phenyl group to which the groups A and X are bonded in positions meta to one another.
 5. Compounds according to claim 1, wherein Ar² is a phenyl group.
 6. Compounds according to claim 1, wherein X is an NH group.
 7. Compounds according to claim 1, wherein n is 0 or
 1. 8. Compounds according to claims 1, wherein R¹ is a hydroxy group.
 9. Compounds according to claims 1, wherein m is 0 or
 1. 10. Compounds according to claim 1, wherein Y is a group of formula CONH.
 11. Compounds according to claims 1, wherein R³ is a group of formula —U—V—W, wherein U is an optionally substituted C₆-C₁₀aryl group or an optionally substituted hetero-aryl group containing from 5 to 10 ring atoms and 1, 2, 3 or 4 hetero atoms selected from O, S and N; V is a direct bond, an oxygen atom, a sulphur atom, a group of formula NR¹¹ (R¹¹ being a hydrogen atom, a C₁-C₄alkyl, C₁-C₄heteroalkyl, C₇-C₁₂aralkyl or C₆-C₁₂heteroaralkyl group), CO, SO, SO₂ or SO₂NH, and W is a hydrogen atom, an alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, alkylcyclo-alkyl, aralkyl, heteroalkylcycloalkyl, heterocyclo-alkyl or heteroaralkyl radical.
 12. Compounds according to claim 11, wherein U is an optionally substituted phenyl group.
 13. Compounds according to claim 11, wherein V is a direct bond or a carbonyl group.
 14. Compounds according to claim 11, wherein W is a C₁-C₄alkyl group, a C₁-C₄heteroalkyl group, an optionally substituted phenyl group, an optionally substituted C₃-C₇cycloalkyl group, an optionally substituted heterocycloalkyl group having 3-7 ring atoms and 1, 2 or 3 hetero atoms (selected from O, S and N) or an optionally substituted heteroaryl group having 5 or 6 ring atoms and 1, 2, 3 or 4 hetero atoms selected from O, S and N.
 15. Pharmaceutical compositions comprising a compound according to claims 1, and, optionally, carrier substances and/or adjuvants.
 16. A method for inhibiting factor Xa by administering a compound of claim
 1. 17. A method for the treatment or prevention of thromboembolic conditions, arterial restenosis, septicaemia, cancer, acute inflammation or other conditions mediated by factor Xa activity comprising administering a compound of claim
 1. 18. A method for preventing or reducing complications relating to thromboembolic conditions in vascular surgery comprising administering a compound of claim 1 prior to, during or following said surgery. 